Method for precipitating finely divided solid particles

ABSTRACT

Comprises a) dissolving a compound C in a fluid A to provide a solution A; b) Thermostatization of said solution A to a temperature ranging between −50° C. and 200° C.; c) Adding a fluid B to said solution A until a pressure P is obtained, and is characterized in that said fluid B at a pressure P is miscible with said solution A, and acts as a co-solvent to form a solution AB; and d) Reduce the pressure of said solution AB so as to produce the precipitation of said compound C.  
     The method permits to obtain particles of average size less than 20 μm, generally less than 10 μm, with a narrow distribution ranging between 1 and 100 μm, generally ranging between 1 and 20 μm, and from a solution, and not a mix, that contains the compound to be precipitated.

FIELD OF THE INVENTION

[0001] This invention relates to a method for precipitating finelydivided solid particles. In particular, this invention relates to a newprocedure that allows particles of average size less than 20 μm to beobtained, with a narrow size distribution ranging between 1 and 100 μm,generally between 1 and 20 μm, from a solution, and not a mixture, thatcontains the compound to be precipitated.

BACKGROUND OF THE INVENTION

[0002] The quality of a large number of industrial products (medicines,explosives, colorants, pigments, cosmetics, polymers, catalysts,chemical products for agriculture, etc.) depends on the physicalcharacteristics (measurement, size distribution, homogeneity,morphology, etc.) of the particles making them up. In conventionalmanufacturing processes finely divided particles are obtained by meansof a sequence of production stages: crystallization or precipitation,drying, triturating or grinding, and homogenisation. Implementing any ofthese stages can be very costly for compounds that are unstable at hightemperature or which undergo degradation when subjected to mechanicalaction. The development of methods for obtaining finely dividedparticles in a single production step is thus of considerabletechnological interest.

[0003] There exist in the state of the art various methods that relateto obtaining finely divided solid particles.

[0004] On one hand, there are methods which use solutions underpressure. Notable amongst the most widely used of such methods is thatdescribed in the U.S. Pat. No. 4,582,731, known as the RESS Procedure,and the method described in international patent WO 9003782, known asthe GAS Procedure.

[0005] On the other hand, there are methods in which cooling of thesolution to be crystallized is caused by the evaporation of a volatilefluid. Notable among the most widely used are the methods described inU.S. Pat. Nos. 4,452,621 and 5,639,441, known as the DCC Procedure.

[0006] There follows a brief description of the mechanism used in eachone of the procedures mentioned to obtain finely divided particles.

[0007] Firstly, in the RESS (Rapid Expansion of a SupercriticalSolution) Procedure the solid to be precipitated is first dissolved in afluid at a pressure and temperature higher than the critical temperatureand pressure. This supercritical solution is then expanded rapidly atatmospheric pressure, with the resulting precipitation of micrometricparticles.

[0008] In this method, supersaturation of the compound in the solutionto be precipitated is due to the rapid fall in the solvating power ofthe supercritical gas caused by the sudden reduction of pressure.

[0009] Secondly, in the GAS (GAS Anti-Solvent) procedure, the gas orfluid under pressure acts as an anti-solvent on a liquid solution of acompound C to be precipitated. Initially, said compound to beprecipitated is dissolved in a fluid A in order to form a solution A,and the solution A is then mixed at a pressure P, with a second fluid B,for example CO₂, which is converted into a gas when the pressure isreduced to atmospheric pressure. In this method the fluid A and thefluid B have to be totally miscible at the pressure P. In the GASprocedure, however, the fluid B acts as an anti-solvent, andprecipitation of the compound C takes place during mixture of thesolution A with the fluid B, at pressure P and temperature T.

[0010] Thirdly, there exists a method in which the cooling of thesolution to be crystallized is caused by the evaporation of a volatilefluid, which is known as the DCC Procedure.

[0011] In a DCC (Direct Contact Cooling) procedure, the evaporation of avolatile fluid (refrigerant) is used to provide the coldness necessaryto permit precipitation. In this case, the degree of homogeneity ofsupersaturation throughout the entire solution to be crystallizeddepends of the quality of mixing between the solution and therefrigerant liquid. The better the mixture the more homogenous thecooling will be, and the narrower the distribution of particle sizeobtained.

[0012] In this crystallization process the solvent in which the compoundto be precipitated is dissolved and the refrigerant fluid are notmiscible and, therefore, a solution is not formed before precipitation.In this case, moreover, the solution A and the fluid B come into contactonce the fluid B has been depressurised.

[0013] One major difference that should be highlighted between themethods of the prior art and that of this application is thatprecipitation of the compound of interest takes place using a mixtureand not using a solution that contains the compound to be precipitated,as is the case in this invention.

DESCRIPTION OF THE INVENTION

[0014] A first objective of this invention is to provide a new methodfor obtaining finely divided solid particles, and therefore particleswith a large surface area, which is of considerable technologicalinterest. The method of the invention permits finely divided solidparticles to be obtained from a solution that contains the compound tobe precipitated. In the prior art, on the other hand, small-sizeparticles are obtained from a mixture which contains the compound to beprecipitated.

[0015] A second objective of the invention is to provide a method whichpermits solid particles of an average size of less than 20 μm, andusually less than 10 μm, to be obtained, with a narrow distribution ofsize of between 1 and 100 μm, usually between 1 and 20 μm.

[0016] A third objective of the invention is to provide a method usefulfor providing finely divided solid particles of a large number ofindustrial products such as drugs, explosives, colorants, pigments,cosmetics, polymers, catalysts, chemical products for agriculture, etc.,which are difficult to make using other procedures existing in the stateof the art or which, in some cases, do not allow the production ofaverage particle sizes of less than 20 μm, and usually less than 10 μm,with a narrow size distribution ranging between 1 and 100 μm, andusually between 1 and 20 μm.

[0017] A fourth objective of the invention is to disclose a method forproviding finely divided solid particles at low cost.

DETAILED DESCRIPTION OF THE INVENTION

[0018] In order to attain the objectives of this invention, the methodfor obtaining finely divided solid particles includes the followingstages:

[0019] a) Dissolving a compound C in a fluid A in order to provide asolution A;

[0020] b) Thermostatization of said solution at a temperature rangingbetween −50° C. and 200° C.

[0021] c) Adding a fluid B to solution A until a pressure P is obtained.

[0022] And it is characterized in that said fluid B is miscible withsaid solution A and acts as a co-solvent in forming a solution AB, sothat no precipitation at all takes place; and then

[0023] d) Reducing the pressure of the solution AB so as to produce ahigh and homogeneous supersaturation of the solution AB and resultingthe precipitation of particles of said compound C.

[0024] The solid particles thus obtained present a narrow distributionof size and an average diameter of less than 20 μm, and usually lessthan 10 μm.

[0025] The faster the speed of depressurisation of the solution AB instage d), the smaller will be the particle size obtained and, therefore,the larger the surface area. This depressurisation causes an intenseevaporation of the fluid B and the consequent fast drop in temperature,which causes the supersaturation of the solution AB and precipitation ofparticles of the compound C dissolved in said solution AB.

[0026] Advantageously, and unlike the RESS procedure of the prior art,in the method of this invention the supersaturation, necessary for theprecipitation to take place, occurs due to the fast and homogeneous fallin the temperature of the solution AB which includes the compound C tobe precipitated. This fall down in temperature takes place homogeneouslythroughout the solution, since this is a solution and not a mixture,owing to depressurisation of the solution AB, initially at a pressure P.During this depressurisation the fluid B is evaporated by boilingcooling the solution AB and causing precipitation of the compound C.

[0027] Unlike in the GAS procedure, in the method of the invention theprecipitation does not take place during the mixing, at pressure P ofthe solution A with the fluid B. In the method of the invention, thefluid B does not act as an anti-solvent, but rather as a co-solvent toform a new solution AB of the compound C at pressure P. Precipitationtakes place when the pressure of the solution AB is reduced suddenly asa result of the cooling caused by evaporation of the fluid B. With themethod of the invention particles of average size of less than 20 μm,and usually less than 10 μm, can be obtained, with a narrow sizedistribution ranging between 1 and 100 μm, and usually between 1 and 20μm.

[0028] As regards the differences between the method of the inventionand the DCC procedure, it should be stressed that although evaporationof a volatile fluid is also used to provide the coldness necessary forthe precipitation to take place, but unlike in the DCC process, in theinvention the fluid B is dissolved at a pressure P in the solution Awhich contains the compound C to be precipitated in order to form a newsolution AB before evaporation and the consequent precipitation of thecompound C take place.

[0029] Thus, in the procedure of the invention, when the pressure isreduced and the fluid B evaporates, a very high degree of homogeneity isachieved in the cooling due to the fact that said depressurisation takesplace in a solution AB.

[0030] Moreover, with the method of the invention a high degree ofsupersaturation of the solution is obtained, which permits theprecipitation of particles of 0.1 to 10 μm with a very narrow sizedistribution. (See FIG. 1, which shows two supersaturation curves inrelation to time. With the method of the invention a high andhomogeneous supersaturation (curve a) is achieved at all points of thesolution and, therefore, during crystallization the nucleation processis enhanced more than crystalline growth, providing small particles witha very narrow size distribution. In the prior art (curve b), for examplein the DCC process, there is a mixture of the solution A and the fluid Band, therefore, the trend in the crystallization curve and the size anddistribution of the particles will depend on the quality of the mixing(shaking speed, design of the shaking apparatus, etc. of the solution Awith the refrigerant fluid)).

[0031] In this invention:

[0032] Compound C is taken to be an industrial product selected from adrug, explosive, colorant, pigment, cosmetic, polymer, catalyst, achemical product for agriculture or other product that may be obtainedin finely divided solid particle form.

[0033] Fluid A is taken to mean any polar or non-polar solvent of thecompound C, whether it be water or an organic solvent or mixtures oforganic solvents that are also miscible with the fluid B. Amongst themost widely used are acetone, methanol, ethanol, ethyl acetate, tolueneor mixtures thereof.

[0034] Fluid B is taken to be any fluid, liquid or supercritical, forexample CO₂, ethane, propane, which, one the one hand, behaves as suchat a process pressure P and temperature T and is also a gas at thedischarge pressure and temperature, normally atmospheric pressure androom temperature. And, on the other hand, said fluid B is miscible withthe fluid A and the solution A or only with the solution A, at a processpressure P and temperature T, so as to provide a solution AB.

[0035] Moreover, in order that the method of the invention for obtainingfinely divided particles can be carried out, the solubility response ofthe compound C in mixtures of fluid A and fluid B, at pressure P andtemperature T, must approximate to a mathematical function, for exampleof the “asymmetric sigmoid” type, which is shown below: $\begin{matrix}{S = \frac{\alpha}{\left\lbrack {1 + {\exp \left\lbrack {- \frac{X_{B} - {{\gamma ln}\left( {2^{1/\delta} - 1} \right)} - \beta}{\gamma}} \right\rbrack}} \right\rbrack^{\delta}}} & {{Equation}\quad 1}\end{matrix}$

[0036] In which S is the solubility of the compound C, expressed inmoles of C per moles of solvent, and X_(B) is the molar fraction offluid B in the solvent (fluid A plus fluid B), that is, X_(B)=molesB/(moles B+moles A), at a pressure P and a temperature T which are shownin FIG. 3 attached.

[0037] The coefficients α, β, γ and δ of equation 1 describe thevariation of S with respect to X_(B), where X_(B) is a value between 0and 1.

[0038] The yield of the method of the invention depends on thesolubility behaviour of the compound C in mixtures of fluid A and fluidB at a pressure P and a temperature T, and therefore of the coefficientsα, β, γ and δ.

[0039] Advantageously, there is a suitable solubility curve when β>0.3and α≈([C_(S)]^(A)−[C_(S)]^(B)), with [C_(S)]^(A) being the saturationconcentration of the compound C in the pure fluid A and [C_(S)]^(B)being the saturation concentration of the compound C in the pure fluidB.

[0040] When the coefficient β<0.01 the requirements for carrying out themethod in accordance with the invention are not fulfilled. For values ofβ between 0.01 and 0.3 the viability of the method depends principallyon the values of coefficient γ, being preferable for absolute values ofγ close to 0, and preferably lower than an absolute value of 0.3.

[0041] Furthermore, the solubility behaviour of the compound C in thesolvent mixture does not depend on the value of the coefficient δ, ascan be seen from Table 1 which is included in the detailed descriptionpart of the figures.

[0042] It should be stressed that, although the function which describesthe solubility of a compound C in a mixture of solvent has beenapproximated to a function of the “asymmetric sigmoid” type, it isobvious that said approximation can be carried out with othermathematical functions that can be approximated to the solubilityfunction which permits the method of the invention to be carried out.

[0043] The evolution of the composition of the compound C-fluid A-fluidB system, at pressure P and temperature T, is shown by a straight linewhose slope is:

[0044] −[C]^(A), where [C]^(A) is the concentration of the compound C inthe fluid A and ordinate at the origin [C]^(A).

[0045] The intersection of said straight line with equation 1 must ariseat a value of X_(B)>0.2, preferably X_(B)>0.4, where X_(B)>is the molarfraction of fluid B in the solvent mixture (fluid A+fluid B). FromX_(B)>0.2 good performance is achieved in precipitation of the compoundC. See FIG. 3.

[0046] Advantageously, in order to maintain the conditions of pressure Pand temperature T within the reactor before carrying out stage d) ofdepressurisation, an inert gas is supplied in the mixing reactor.

[0047] In this invention, inert gas is taken to mean any gas that doesnot interfere with the solubility between the compound C and fluid A andfluid B and does not modify their chemical composition. Notable amongthe most widely used are nitrogen, helium and argon.

[0048] This invention provides a method for obtaining particles of anaverage size smaller than 10 μm and a very narrow size distribution. SeeFIGS. 8 and 11.

[0049] Advantageously, and in accordance with the method of theinvention, the making of a solution AB permits the cooling of saidsolution AB to be carried out by depressurisation in a whollyhomogeneous way, that is, almost at molecular level. This promotes ahigh degree of nucleation compared with the crystalline growth withwhich particles of average size less than 20 μm, and generally less than10 μm are obtained, in addition to a narrow distribution of particlesize. See FIG. 1 on the crystallization curve.

[0050] With the procedures described in the prior art it is not possibleto obtain the high degree of nucleation that is obtained with the methodof the invention, since it is a solution and not a mixture. In themethods of the prior art the cooling of the mixture that contains thecompound to be precipitated arises through evaporation of a fluid whichis in more or less close contact with the mixture that contains saidcompound to be precipitated. There has nevertheless been no descriptionor suggestion that the evaporation of the fluid that permits the coolingof the solution is miscible with solution A, in such a way that a newsolution AB is formed. In the prior art, before depressurising in orderto cool the mixture two phases exist even where mechanical means havebeen used, such as shaking, that bring both phases into intimatecontact, and therefore the refrigerating effect that can causeevaporation of one of these phases cannot be compared with therefrigerating effect caused by evaporation of the fluid B dissolved inthe solution AB.

DESCRIPTION OF THE FIGURES

[0051]FIG. 1 shows two supersaturation curves in relation to time.

[0052]FIG. 2 provides a schematic representation of an installation forcarrying out the method of the invention.

[0053]FIG. 3 shows the variation in the solubility of a compound C withthe composition of the solvent (fluid A and fluid B) at a pressure P anda temperature T with values of the coefficients in accordance withequation 1 that permit the method to be carried out according to theinvention.

[0054]FIG. 4 shows the variation in the solubility of a compound C withthe composition of the solvent at a pressure P and a temperature T withvalues of the coefficients in accordance with equation 1 that do notpermit the method to be carried out according to the invention.

[0055] Also included below are the figures corresponding to the examplesof this invention.

[0056]FIGS. 5, 6, 7, 9 and 12 show the curves of variation of thesolubility in moles of compound C/moles of solvent (fluid A+fluid B)with the molar fraction of fluid B in the solvent.

[0057]FIGS. 8, 10 and 11 show the distribution of size of the particlesusing the Coulter technique using light dispersion.

[0058] The geometrical characteristics of the particles of precipitate(size and distribution of sizes) are measured by the Coulter techniquethat uses light dispersion with Fourier lenses. Thus, by “particle size”is meant the value of the median of the curve of distribution ofparticles, in % in volume, and by “distribution of sizes” is meant thevalue of the standard deviation from the same curve.

DETAILED DESCRIPTION OF THE FIGURES

[0059]FIG. 1 shows two supersaturation curves in relation to time (t).

[0060] Said FIG. 1 presents three differentiated zones: zone I in whichthere is no crystalline growth; zone II in which there is crystallinegrowth but not nucleation; and zone III in which there is nucleation.

[0061] From FIG. 1 it can be observed that in accordance with the methodof the invention (curve a), said supersaturation curve develops in zoneIII over a brief period of time, and so there exists a high nucleation.Moreover, according to the method of the invention there is littlecrystalline growth, zone II, when compared with the crystalline growthwhich takes place according to the procedures of the prior art, andtherefore a high number of solid particles

[0062]FIG. 2 shows a schematic representation of an installation forcarrying out the method of the invention which allows particles with avery narrow size distribution to be obtained, of a size less than 20 μm,and generally less than 10 μm.

[0063] The equipment includes a tank 1 which contains the fluid B,connected through the pipe 2 to a pump 3 which delivers the fluid B athigh pressure. Addition of the fluid B in the mixing reactor 7, in whichsolution A (compound C and fluid A) is situated, can be carried outthrough the upper part, through valves 4 and 6, or through the lowerpart through valves 4 and 5. The addition to the mixing reactor 7 of aninert gas which is in a tank 8 is controlled through valve 9. Thesolution at pressure P, that had been prepared in the reactor 7, passesto the filter 11 through the valve 10, where a first filtering atpressure P is implemented through the filter 11.

[0064] This filter is not necessary for carrying out the method of theinvention, since no precipitation of compound C takes place in thereactor mixture. It can nevertheless be useful to fit such a filter inorder to eliminate possible solid residue in the subsequent filtering.

[0065] At the outlet from the filter 11 and after passing through thevalve 12, the solution undergoes a rapid reduction of pressure down toatmospheric pressure, with the consequent precipitation of particles.During the filtering at atmospheric pressure, these particles areretained on the filter 13 and the mother liquor is channelled to thetank 15 through the valve 14.

[0066] As FIG. 3 shows, fluid B can be added to solution A (compound Cin fluid A), with concentration of [C]^(A) lower than the saturationconcentration [Cs]^(A) at temperature T, until a new solution AB ofmolar fraction X_(B)(1) is formed, without precipitation by “saltingout” occurring, that is, precipitation by addition of fluid B.

[0067] The rapid reduction of pressure of the new solution AB leads to asharp fall in temperature, homogeneously throughout the solution, andthis causes precipitation of the compound C. The uniform and fastreduction of temperature at all points in the solution rapidly producesconsiderable supersaturation, thus boosting the nucleation process asagainst crystalline growth and the obtaining of particles of averagesize of less than 10 μm and with a very narrow size distribution.

[0068]FIG. 4 shows the variation in solubility of a compound C with thesolvent mixture (fluid A and fluid B) at a pressure P and temperature T,for which a method in accordance with the invention cannot be carriedout.

[0069] If the variation of solubility of a compound C with the solventmixture (fluid A and fluid B) is as shown in FIG. 4, a precipitation inaccordance with the method of the invention cannot be carried out. Inthis case, when the fluid B is added to the initial solution A, atconcentration [C]^(A) at pressure P and temperature T, precipitation by“salting out” will occur before having mixed a sufficient quantity offluid B with solution A in order to obtain a homogeneous solution AB.

[0070] There follows a more detailed description of the figurescorresponding to the examples.

[0071]FIG. 5 shows the position of the acetaminophen-ethanol-CO₂ mixtureat 100 bar and 42° C. immediately prior to depressurisation (stage d),of example 1 (filled-in spot), in relation to the solubility curve ofthe acetaminophen in ethanol-CO₂ mixtures at 100 bar and 42° C. When thesolubility curve shown in FIG. 1 is adjusted by means of Equation 1 thefollowing values were obtained for the coefficients: α=0.092; β=0.34;γ=−0.14 and δ=1.3.

[0072]FIG. 6 shows the position of the acetaminophen-ethanol-CO₂ mixtureat 100 bar and 42° C. immediately prior to depressurisation, of example2, in relation to the solubility curve of the acetaminophen inethanol-CO₂ mixtures at 100 bar and 42° C. When the solubility curveshown in the figure is adjusted by means of Equation 1 the followingvalues were obtained for the coefficients: α=0.092; β=0.34; γ=−0.14 andδ=1.3.

[0073]FIG. 7 shows the position of the “solvent blue 35”-acetone-CO₂mixture at 60 bar and 25° C. immediately prior to depressurisation, ofexample 3, with respect to the solubility curve of the “solvent blue 35”in acetone-CO₂ mixtures at 60 bar and 25° C. When the solubility curvewas adjusted to Equation 1 the following values were obtained: α=0.018;β=0.48; γ=−0.25 and δ=71.

[0074]FIG. 8 shows the analysis of particle size by the COULTERtechnique using light dispersion of example 3, in accordance with themethod of the invention.

[0075]FIG. 9 shows the position of the mixture of “solvent blue35”-acetone-CO₂ mixture at 60 bar and 25° C. immediately prior todepressurisation, of example 4, with respect to the solubility curve ofthe “solvent blue 35” in acetone-CO₂ mixtures at 60 bar and 25° C. Whenthe solubility curve was adjusted to Equation 1 the following valueswere obtained: α=0.018; β=0.48; γ=−0.25 and δ−71.

[0076]FIG. 10 shows the analysis of particle size by the COULTERtechnique using light dispersion of the fraction of precipitation ofparticles of example 4, in accordance with the GAS procedure of theprior art.

[0077]FIG. 11 shows the analysis of particle size by the COULTERtechnique using light dispersion of the fraction of precipitation ofparticles of example 4, in accordance with the method of the invention.

[0078]FIG. 12 shows the position of the acetaminophen-acetone-CO₂mixture at 100 bar and 42° C. immediately prior to depressurisation, ofexample 5, in relation to the solubility curve of the acetaminophen inacetone-CO₂ mixtures at 100 bar and 42° C. When the solubility curve wasadjusted to Equation 1 the following values were obtained for thecoefficients: α=0.12; β=0.01; γ=0.23 and δ=2.3.

[0079] Provided below is Table 1, which gathers together all the valuesof the variables of equation 1 obtained in accordance with the figurespertaining to the examples of the invention.

[0080] It is advantageous if the solution AB to be depressurised is in aposition close to the curve of the variation of solubility with thecomposition of the solvent and with values of X_(B)>0.2. TABLE 1 Exampleno. α β γ δ 1 0.092 0.34 −0.14 1.3 2 0.092 0.34 −0.14 1.3 3 0.018 0.48−0.25 71 4 0.018 0.48 −0.25 71 5 0.12 −0.01 −0.23 2.3

PREFERRED EMBODIMENT OF THE INVENTION

[0081] There follow below details of a preferred embodiment of themethod of the invention schematised in FIG. 2.

[0082] 1. Introduction into the reactor of mixture 7, at a temperatureT, of a certain quantity (V_(i)) of a solution A of the compound C to beprecipitated, with the fluid A being water or an organic solvent ofmixtures of same such as acetone, methanol, ethanol, ethyl acetate,toluene, etc.

[0083] 2. Formation in the reactor 7 of a new liquid solution AB, atpressure P and temperature T, by means of addition onto solution A of afluid B, liquid or supercritical, for example CO₂, ethane, propane,etc., which is a gas at atmospheric pressure and is miscible with thefluid A at pressure P. The addition of the fluid B is implemented, viathe pump 3, through the lower part of the reactor 7 and keeping thevalves 4 and 5 open and all the others closed. The addition ends whenthere is a single liquid phase in the reactor 7 at pressure P.

[0084] 3. Opening of valve 10, in order to establish the same pressure Pin the reactor 7 and in the filter 11.

[0085] 4. Depressurisation of the solution AB and filtering of theparticles precipitated: the valve 9 is opened in order to permit theentry of N₂ at the pressure P. The valves 4 and 5 are closed in order tocut off the supply of CO₂. Valve 14 is opened in order to ensure thatthe filter 13 is at atmospheric pressure. The valve 12 is openedgradually in order to start depressurisation of the solution AB. At thefilter 11, filtering is carried out at the pressure P and anyprecipitate formed during the mixing of solution A with solution B iscollected. At filter 13, filtering is carried out at atmosphericpressure, and the particles formed in it by the method of the inventionare retained. The mother liquor is collected in the tank 15.

[0086] 5. Washing of the precipitate: the valve 12, and then valve 14,are closed. The supply of N₂ is shut off by closing valve 9. The supplyof CO₂ through the upper part of the reactor 7 is opened up, by openingvalves 4 and 6. Valve 12 is opened gradually until the filter 13 is atthe desired washing pressure P. This pressure is maintained by means ofcontrolled opening of the valve 14. A certain flow of CO₂ is maintainedat pressure P through the filter 11, and at pressure P1 through filter13, in order to wash the precipitates contained in both filters.

[0087] 6. Isolation of filter 13: the valve 12 is closed, the supply ofCO₂ is cut off by the closing of valves 4 and 5, the filter 13 isdepressurised through valve 14, and the filter 13 is detached from therest of the equipment in order to be able to recover the precipitatecontained in it.

[0088] 7. The rest of the equipment is depressurised through valve 12.

EXAMPLES Example 1

[0089] In the mixing reactor 7 of 2-litre capacity are placed 1,750 mlof a solution of the drug acetaminophen in ethanol with a concentrationin relation to saturation of 80%. Over this solution is added CO₂ at aflow rate of 7 kg/h until the pressure in the reactor 7 reaches 100 bar.The temperature is kept constant at 42° C. throughout the entireprocess. The new acetaminophen-ethanol-CO₂ mixture is left to stabilizeat 100 bar and 42° C. for 10 minutes (see FIG. 5). The supply of CO₂ isshut off and addition of N₂ through the upper part of the reactor isstarted through valve 6, keeping the pressure and temperature constant.Depressurisation of the solution, with resulting rapid evaporation ofthe CO₂ and sudden cooling of the solution homogeneously at all partsthereof occurs when valve 12 is opened, valve 14 having been openedpreviously. The precipitate of acetaminophen produced according to themethod of the invention is collected in the filter 13 at atmosphericpressure and washed with CO₂ at 40 bar. The size distribution of theparticles of precipitate obtained according to the method of theinvention shows an average size of 15 μm, with standard deviation of 18μm. The yield of the process is 25%.

Example 2

[0090] The presence of the filter 11 in the arrangement of the equipmentused for carrying out precipitations according to the method of theinvention is justified in those cases in which it is appropriate to workwith compound C-fluid A-fluid B mixtures situated above the solubilitycurve. In such cases there is a possibility that part of theprecipitation of the compound C is by GAS process (WO 9003782), and, ifthis is the case, it would be collected in filter 11. The presence ofthe filter 11 thus improves this invention, since whenever necessary,the precipitate produced by GAS process can be separated from thatproduced by the method of the invention.

[0091] In the mixing reactor 7 of 2-litre capacity are placed 1,600 mlof a solution of the drug acetaminophen in ethanol with a concentrationin relation to saturation of 80%. Over this solution is added CO₂ at aflow rate of 7 kg/h until the pressure in the reactor 7 reaches 100 bar.The temperature is kept constant at 42° C. throughout the entireprocess. The new acetaminophen-ethanol-CO₂ mixture is left to stabilizeat 100 bar and 42° C. for 10 minutes (see FIG. 6). The supply of CO₂ isshut off and addition of N₂ through the upper part of the reactor isstarted through valve 6, keeping the pressure and temperature constant.Depressurisation of the solution, with resulting rapid evaporation ofthe CO₂ and sudden cooling of the solution, equally intensely at allparts thereof, occurs when valve 12 is opened, valve 14 having beenopened previously. The precipitate of acetaminophen produced by GASprocess is collected in the filter 11 at 100 bar pressure. Theprecipitate of acetaminophen produced according to the method of theinvention is collected in the filter 13 at atmospheric pressure. Bothare washed with CO₂ at 40 bar. The size distribution of the particles ofprecipitate obtained by GAS process has an average size of 50 μm, withstandard deviation of 30 μm The size distribution of the particles ofprecipitate obtained by the method of the invention has an average sizeof 15 μm, with standard deviation of 15 μm. The yield of the GAS processis 5%, while that of the method of the invention is 30%.

Example 3

[0092] In the mixing reactor 7 of 2-litre capacity is placed 1,400 ml ofa solution of the colorant “solvent blue 35” in acetone with aconcentration in relation to saturation of 80%. Over this solution isadded CO₂ at a flow rate of 7 kg/h until the pressure in the reactor 7reaches 60 bar. The temperature is kept constant at 25° C. throughoutthe entire process. The new “solvent blue 35”-acetone-CO₂ mixture isleft to stabilize at 60 bar and 25° C. for 10 minutes (see FIG. 7). Thesupply of CO₂ is shut off and addition of N₂ through the upper part ofthe reactor is started through valve 6, keeping the pressure andtemperature constant. Depressurisation of the solution, with resultingrapid evaporation of the CO₂ and sudden cooling of the solution, equallyintensely at all parts thereof, occurs when valve 12 is opened, withvalve 14 having been opened previously. The precipitate of “solvent blue35” colorant produced by the method of the invention is collected infilter 13 at atmospheric pressure and washed with CO₂ at 40 bar. Thedistribution of precipitate particle size obtained using the method ofthe invention (FIG. 8) has an average of 5 μm, with standard deviationof 3 μm. The yield of the process is 80%.

Example 4

[0093] In the following example, the presence of the filter 11 is onceagain justified.

[0094] In the mixing reactor 7 of 2-litre capacity is placed 640 ml of asolution of the colorant “solvent blue 35” in acetone with aconcentration in relation to saturation of 80%. Over this solution isadded CO₂ at a flow rate of 7 kg/h until the pressure in the reactor 7reaches 60 bar. The temperature is kept constant at 25° C. throughoutthe entire process. The new “solvent blue 35”-acetone-CO₂ mixture isleft to stabilize at 60 bar and 25° C. for 10 minutes (see FIG. 9). Thesupply of CO₂ is shut off and addition of He through the upper part ofthe reactor is started through valve 6, keeping the pressure andtemperature constant. Depressurisation of the solution, with resultingrapid evaporation of the CO₂ and sudden cooling of the solution, equallyintensely at all parts thereof, occurs when valve 12 is opened, withvalve 14 having been opened previously. The precipitate of “solvent blue35” colorant produced by GAS process is collected in filter 11 at 60 barpressure. The precipitate of colorant produced by the method of theinvention is collected in filter 13 at atmospheric pressure. Both arewashed with CO₂ at 40 bar. The distribution of precipitate particle sizeobtained using the GAS process (FIG. 10) has an average size of 70 μm,with standard deviation of 65 μm. The distribution of precipitateparticle size obtained using the method of the invention (FIG. 11) hasan average of 4 μm, with standard deviation of 6 μm. The yield of theGAS process is 5%, while that of the process of the invention is 70%.

Example 5

[0095] The following example is equivalent to Example 2 in relation tothe working conditions and arrangement of the equipment, but in thiscase the fluid A is acetone instead of ethanol. The solubility curves ofthe acetaminophen-ethanol-CO₂ and acetaminophen-acetone-CO₂ systems arecompletely different (compare FIG. 6 and FIG. 12). This is the reasonwhy in Example 2 precipitation is obtained by the method of theinvention, while in Example 5 GAS process precipitation is obtained.

[0096] In the mixing reactor 7 of 2-litre capacity are placed 1,600 mlof a solution of the drug acetaminophen in acetone with a concentrationin relation to saturation of 80%. Over this solution is added CO₂ at aflow rate of 7 kg/h until the pressure in the reactor 7 reaches 100 bar.The temperature is kept constant at 42° C. throughout the entireprocess. The new acetaminophen-acetone-CO₂ mixture is left to stabilizeat 100 bar and 42° C. for 10 minutes (see FIG. 12). The supply of CO₂ isshut off and addition of N₂ through the upper part of the reactor isstarted through valve 6, keeping the pressure and temperature constant.Depressurisation of the solution, with resulting rapid evaporation ofthe CO₂ and sudden cooling of the solution, homogeneously at all partsthereof, occurs when valve 12 is opened, valve 14 having been openedpreviously. The precipitate of the acetaminophen produced by GAS processis collected in the filter 11 at 100 bar pressure and is washed with CO₂at 40 bar. Precipitate produced by the method of the invention is notcollected in filter 13. The size distribution of the particles ofprecipitate obtained by GAS process shows an average size of 50 μm, withstandard deviation of 39 μm. The yield of the GAS process is 60%.

Example 6

[0097] In the mixing reactor 7 of 2-litre capacity are placed 1,350 mlof a solution of the drug “aspirin” in acetone with a concentration inrelation to saturation of 60%. Over this solution is added CO₂ at a flowrate of 7 kg/h until the pressure in the reactor 7 reaches 70 bar. Thetemperature is kept constant at 25° C. throughout the entire process.The new “aspirin”-acetone-CO₂ mixture, with a molar fraction of CO₂ of0.6, is left to stabilize at 70 bar and 25° C. for 10 minutes. Thesupply of CO₂ is shut off and addition of N₂ through the upper part ofthe reactor is started through valve 6, keeping the pressure andtemperature constant. Depressurisation of the solution, with resultingrapid evaporation of the CO₂ and sudden cooling of the solution, atequal intensity in at all parts thereof, occurs when valve 12 is opened,valve 14 having been opened previously. The precipitate of the medicine“aspirin” produced by method of the invention is collected in the filter13 at atmospheric pressure and is washed with CO₂ at 40 bar. The sizedistribution of the particles of precipitate obtained by the method ofthe invention shows an average size of 14 μm, with standard deviation of15 μm. The yield of the process is 40%.

Example 7

[0098] In the mixing reactor 7 of 2-litre capacity are placed 1,300 mlof a solution of the organic compound “stearic acid” in ethyl acetatewith a concentration in relation to saturation of 80%. Over thissolution is added CO₂ at a flow rate of 7 kg/h until the pressure in thereactor 7 reaches 100 bar. The temperature is kept constant at 25° C.throughout the entire process. The new “stearic acid”-ethyl acetate-CO₂mixture, with a molar fraction of CO₂ of 0.6, is left to stabilize at100 bar and 25° C. for 10 minutes. The supply of CO₂ is shut off andaddition of N₂ through the upper part of the reactor is started throughvalve 6, keeping the pressure and temperature constant. Depressurisationof the solution, with resulting rapid evaporation of the CO₂ and suddencooling of the solution, at equal intensity in at all parts thereof,occurs when valve 12 is opened, valve 14 having been opened previously.The precipitate of stearic acid produced by method of the invention iscollected in the filter 13 at atmospheric pressure and is washed withCO₂ at 40 bar. The size distribution of the particles of precipitateobtained by the method of the invention shows an average size of 2 μm,with standard deviation of 2 μm. The yield of the process is 70%.

Example 8

[0099] In the mixing reactor 7 of 2-litre capacity are placed 900 ml ofa solution of the organic compound “methenamine” in ethanol with aconcentration in relation to saturation of 90%. Over this solution isadded CO₂ at a flow rate of 7 kg/h until the pressure in the reactor 7reaches 100 bar. The temperature is kept constant at 25° C. throughoutthe entire process. The new “methenamine”-ethanol-CO₂ mixture, with amolar fraction of CO₂ of 0.7, is left to stabilize at 100 bar and 25° C.for 10 minutes. The supply of CO₂ is shut off and addition of N₂ throughthe upper part of the reactor is started through valve 6, keeping thepressure and temperature constant. Depressurisation of the solution,with resulting rapid evaporation of the CO₂ and sudden cooling of thesolution, at equal intensity in at all parts thereof, occurs when valve12 is opened, valve 14 having been opened previously. The precipitate of“methenamine” produced by method of the invention is collected in thefilter 13 at atmospheric pressure and is washed with CO₂ at 40 bar. Thesize distribution of the particles of precipitate obtained by the methodof the invention shows an average size of 8 μm, with standard deviationof 10 μm. The yield of the process is 60%.

1. Method for obtaining finely divided solid particles which comprises:a) Dissolving a compound C in a fluid A in order to provide a solutionA; b) Thermostatization of said solution A at a temperature rangingbetween −50° C. and 200° C.; c) Adding a fluid B to said solution Auntil a pressure P is obtained. characterised in that said fluid B atpressure P is miscible with said solution A and acts as a co-solvent informing a solution AB; and d) Reducing the pressure of said solution ABso as to produce the precipitation of said compound C.
 2. Method asclaimed in claim 1, characterized in that said compound C is selectedfrom a drug, explosive, colorant, pigment, cosmetic, polymer, catalyst,a chemical product for agriculture or other product that may be obtainedin finely divided solid particle form.
 3. Method as claimed in claim 1,characterized in that said fluid A is a polar or non-polar solvent suchas water or an organic solvent or mixtures of organic solvents that aremiscible with the fluid B.
 4. Method as claimed in claim 3, where saidfluid A is water, acetone, methanol, ethanol, ethyl acetate, toluene ormixtures thereof.
 5. Method as claimed in claim 1, characterized in thatsaid fluid B is any liquid or supercritical fluid which, on the onehand, behaves as such at a pressure P and temperature T and is also agas at the discharge pressure and temperature, and on the other hand, ismiscible with said fluid A and said solution A or only with saidsolution A, so as to provide a solution AB.
 6. Method as claimed inclaim 1, characterised in that before carrying out stage d) an inert gasis added the solution AB.
 7. Method as claimed in claim 6, in which saidinert gas is any gas that goes not interfere with the solubility ofcompound C in fluid A and fluid B or modify their chemical composition.8. Method as claimed in claim 6 or claim 7, in which said inert gas isselected from among nitrogen, helium or argon.
 9. Method as claimed inclaim 1, characterised in that the solubility response of said compoundC in the solvent, fluid A and fluid B, at pressure P and temperature T,approximates to a mathematical function of “asymmetric sigmoid” type,which is shown below: $\begin{matrix}{S = \frac{\alpha}{\left\lbrack {1 + {\exp \left\lbrack {- \frac{X_{B} - {{\gamma ln}\left( {2^{1/\delta} - 1} \right)} - \beta}{\gamma}} \right\rbrack}} \right\rbrack^{\delta}}} & {{Equation}\quad 1}\end{matrix}$

In which: S is the solubility of the compound C, expressed in moles of Cper moles of solvent; X_(B) is the molar fraction of fluid B in thesolvent, at a pressure P and a temperature T, and β>0.01, γ=0 andα≈([C_(S)]^(A)−[C_(S)]^(B)), with [C_(S)]^(A) being the saturationconcentration of the compound C in the fluid A and [C_(S)]^(B) being thesaturation concentration of the compound C in the fluid B, independentlyof the value of δ.
 10. Method as claimed in claim 9, characterised inthat β>0.3.
 11. Method as claimed in claim 9, characterised in that|γ|<0.3.
 12. Method as claimed in any of the previous claims in whichthe finely divided solid particles have an average particle diameter ofless than 20 μm, generally less than 10 μm, and a size distributionranging between 1 and 100 μm, generally between 1 and 20 μm.